Natriuretic peptides promote glucose uptake in a cGMP-dependent manner in human adipocytes

Marine Coué,Cedric Moro,Valentin Barquissau,Aline Mairal,Katie Louche,Nathalie Viguerie,Pauline Morigny,Corinne Lefort,Christian Carpéné,Peter Arner,Mikael Rydén,Dominique Langin

doi:10.1038/s41598-018-19619-0

Abstract

Robust associations between low plasma level of natriuretic peptides (NP) and increased risk of type 2 diabetes (T2D) have been recently reported in humans. Adipose tissue (AT) is a known target of NP. However it is unknown whether NP signalling in human AT relates to insulin sensitivity and modulates glucose metabolism. We here show in two European cohorts that the NP receptor guanylyl cyclase-A (GC-A) expression in subcutaneous AT was down-regulated as a function of obesity grade while adipose NP clearance receptor (NPRC) was up-regulated. Adipose GC-A mRNA level was down-regulated in prediabetes and T2D, and negatively correlated with HOMA-IR and fasting blood glucose. We show for the first time that NP promote glucose uptake in a dose-dependent manner. This effect is reduced in adipocytes of obese individuals. NP activate mammalian target of rapamycin complex 1/2 (mTORC1/2) and Akt signalling. These effects were totally abrogated by inhibition of cGMP-dependent protein kinase and mTORC1/2 by rapamycin. We further show that NP treatment favoured glucose oxidation and de novo lipogenesis independently of significant gene regulation. Collectively, our data support a role for NP in blood glucose control and insulin sensitivity by increasing glucose uptake in human adipocytes. This effect is partly blunted in obesity.

Highlights

Atrial- and B-type Natriuretic Peptides (NP), ANP and BNP respectively, are well-known cardiovascular hormones produced by the right atria of the heart in response to mechanical stretch
We found a significant decrease of adipose guanylyl cyclase-A (GC-A) expression in prediabetic (PreD, defined as impaired fasting glucose or glucose tolerance) and type 2 diabetic subjects (T2D) compared to individuals with normal glucose tolerance (NGT) (Fig. 1D), while no change was observed for NP clearance receptor (NPRC) (Fig. 1E)
Adipose GC-A mRNA level was reduced with increasing quartiles of HOMA-IR, demonstrating that the most insulin resistant individuals have the lowest adipose GC-A gene expression (Supplemental Fig. 1A), while no significant change was observed for NPRC (Supplemental Fig. 1B)

Summary

Introduction

Atrial- and B-type Natriuretic Peptides (NP), ANP and BNP respectively, are well-known cardiovascular hormones produced by the right atria of the heart in response to mechanical stretch They signal through the guanylyl cyclase-A (GC-A), a transmembrane receptor exhibiting guanylyl cyclase activity[1,2,3,4]. A causal link between reduced plasma NP levels in obesity, insulin resistance and T2D has not yet been demonstrated It is so far unclear how NP may influence blood glucose control in humans. The aim of the present study was: 1) to explore the relationships between adipose NP receptor expression and obesity, insulin resistance and T2D, and 2) to determine the impact of NP on glucose metabolism in human adipocytes. Our data demonstrate a robust link between adipose GC-A expression and insulin sensitivity, and highlight a novel biological pathway in human adipocytes by which NP promote glucose uptake and metabolism in a cGMP-dependent manner

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Conclusion